The subject of this program project is islet transplantation, with a focus upon optimizing the source of insulin producing cells and genetically modifying these cells to withstand xenograft rejection and autoimmunity. Porcine islet cells will be altered by gene transfer with viral vectors to modulate the immune reaction locally and to enhance beta cell defense against apoptosis. An interdisciplinary team has been assembled to propose four collaborative projects and two scientific cores, with the following goals: Project 1 (Weir/Bonner-Weir/Mulligan): To better understand the development of porcine neonatal pancreatic endocrine cells and to optimize their potential for transplantation. To establish the conditions for genetic modification of rat and porcine islet cells using different viral vector systems to provide long term expression. Project 2 (lipes): To genetically engineer cells of the intermediate lobe of the pituitary to produce insulin in response to physiological stimuli such as glucose and gut hormone. This genetic modification will be accomplished by transgenesis and the use of viral vectors. Project 3 (Ferran/Bach): To test the hypothesis that cell death from apoptosis is an important pathway for immunemediated islet graft failure, and that protection against this process can be accomplished by transduction into beta cells of genes that are anti-apoptic and cytokine inhibitors. Project 4 (Auchincloss): To examine the mechanisms by which xenogeneic islets are rejected through the use of murine and primate models. To evaluate humoral rejection, direct versus indirect T cell responses, and the relative consequences of Th1 and Th2 cytokine production. Scientific Core B (Weir): To provide rodent and porcine (both neonatal and adult) islets. Scientific Core C (Hancock/Bonner-Weir): To provide services to evaluate the immunopathologyy, apoptosis and morphometry of islets.